Palladium(II)-catalyzed enantioselective arylation of α-imino esters

Article abstract of DOI:10.1021/jo301423e

A protocol for Pd(II)-catalyzed asymmetric arylation of N-aryl imino esters has been developed. The method affords a practical and direct access to chiral arylglycine derivatives in good yields and with high enantioselectivities.

Full text of DOI:10.1021/jo301423e

Article
pubs.acs.org/joc
Palladium(II)-Catalyzed Enantioselective Arylation of α‑Imino Esters
Jiayan Chen,† Xiaoxia Lu,‡ Wenyong Lou,§ Yong Ye,† Huanfeng Jiang,† and Wei Zeng*,†
†School of Chemistry and Chemical Engineering, South China University of Technology, No. 381, Wushan Road, Tianhe District,
Guangzhou 510640, People's Republic of China
‡Chengdu Institute of Biology, Academy of Sciences, Chengdu 610041, People's Republic of China
§College of Light Industry and Food Sciences, South China University of Technology, Guangzhou 510640, People's Republic of
China
S
* Supporting Information
ABSTRACT: A protocol for Pd(II)-catalyzed asymmetric
arylation of N-aryl imino esters has been developed. The
method affords a practical and direct access to chiral
arylglycine derivatives in good yields and with high
enantioselectivities.
aryl-C-acylimines (2) which are readily produced from primary
arylamines and glyoxylates (see Scheme 1).
INTRODUCTION
■
Chiral arylglycines are fundamental building blocks of many
pharmacologically active molecules1 such as amoxicillins,
nocardicins, cephalecins, and glycopeptide antibiotics. Optically
active α-amino acids are also commonly utilized as auxiliaries
and catalysts in modern organic synthesis.2 Therefore, the
exploration of a relatively straightforward methodology that can
produce natural and unnatural α-amino acid derivatives with
high levels of enantioselectivity is an important undertaking.3
The asymmetric addition of metallic or nonmetallic reagents
to imines provides an efficient approach to various
enantioenriched amines.4 Among these extensive chiral
amine-forming reactions, the addition of arylboronic acids to
imines has attracted significant interest, because it capitalizes on
the compatibility of diverse arylboronic acids with various
functional groups. Although the transition-metal- or organo-
catalyzed addition of arylboronic acids to N-acyl-C-arylimine
such as N-sulfonyl, N-diphenylphosphinoyl, and N-sulfinyl
imines has recently been well developed and produces α-chiral
amines with excellent enantioselectivity,5 this transformation
could not provide chiral amino acids even through further
reactions. Nevertheless, considering that α-imino esters have
served as a cheap and easily available source of amino and
carboxyl groups of amino acids,6 Ellman,7 Lu,8 and Xu9
successively realized the diastereoselective synthesis of α-amino
acid derivatives via Rh-, Pd-, and In-catalyzed addition of aryl-
or alkenylboronic acids to chiral starting material N-sulfinyl
iminoacetates, respectively. Soon thereafter, Schaus and co-
workers further developed a chiral biphenol-catalyzed asym-
metric Petasis reaction of organoboronic acids, secondary
amines, and glyoxylates to give chiral glycine derivatives,10 but
most of the optically active α-amino acid derivatives were only
limited to those containing alkenyl groups at the α-position.11
Herein we report an efficient asymmetric synthesis of
arylglycines (up to 99% ee) based on palladium-catalyzed
highly enantioselective addition of arylboronic acids (1) to N-
Scheme 1. Pd-Catalyzed Asymmetric Arylation of α-Imino
Esters
RESULTS AND DISCUSSION
■
We initially conducted the Pd(II)-catalyzed addition of
arylboronic acids to N-aryl-C-acylimines using (4-methoxy-
phenylimino)acetic acid ethyl ester (1a) and phenylboronic
acid (2a) as the model substrates to screen the reaction
conditions for the optimization of the catalyst, ligand, solvent,
and temperature under an Ar atmosphere. As shown in Table 1,
in the absence of any ligand, the Pd(II)-catalyzed arylation of
N-aryl-C-acylimine 1a afforded only trace amounts of the
racemic (4-methoxyphenylamino)phenylacetic acid ethyl ester
(3a) at 60 °C (<10% yield) (entries 1 and 2). In contrast,
moderate to good yields occurred under Pd(II)/2,2′-bipyridine
(bipy) conditions, possibly because bipy can enhance the
nucleophility of arylpalladium species and accelerate the
addition reaction (entries 3−6).8 Among them, the Pd(OAc)2
(5 mol %)/bipy (5 mol %) system (60 °C, 10 h) gave a good
yield (78%) of the desired α-amino ester (3a) (entry 4) (see
the Supporting Information for more details). Encouraged by
these positive results, we further investigated the effect of chiral
bidentate phosphine- or nitrogen-containing ligands on the
enantioselectivity of this transformation. We quickly found that
chiral pyridine-oxazoline ligands (PYOX; L6 and L7) and
Received: July 19, 2012
© XXXX American Chemical Society
A
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a
Table 1. Optimization Results for the Arylation of C-Acylimine (1a) and Boronic Acid (2a) with Pd(II)/Ligand as the Catalyst
b
c
entry
PdX2·ligand
x
time (h), temp (°C)
yield (%)
ee (%)
1
Pd(TFA)2
5
10, 60
10, 60
10, 60
10, 60
10, 90
10, 40
10, 60
24, 60
48, 60
48, 60
16, 60
16, 60
16, 60
48, 60
24, 60
24, 60
24, 60
24, 50
<5
9
2
Pd(OAc)2
5
5
3
Pd(TFA)2·bipy
Pd(OAc)2·bipy
Pd(OAc)2·bipy
Pd(OAc)2·bipy
Pd(OAc)2·L1
Pd(OAc)2·L2
Pd(OAc)2·L3
Pd(OAc)2·L4
Pd(OAc)2·L5
Pd(OAc)2·L6
Pd(OAc)2·L7
Pd(OAc)2·L8
Pd(OAc)2·L9
Pd(OAc)2·L10
Pd(OAc)2·L10
Pd(OAc)2·L10
33
4
5
78
5
5
64
6
5
47
7
5
trace
<10
0
nd
nd
nd
16
34
76
80
nd
90
95
96
95
8
5
9
5
10
11
12
13
14
15
16
17
18
5
14
5
71
5
59
5
71
5
trace
65
5
5
53
d
10
10
67 (13 )
81
a
Reactions were run with 1a (0.1 mmol), 2a (0.1 mmol), Pd(II) salt (5−10 mol %)/L (5−10 mol %), and CH3NO2 (3.0 mL) under Ar in a sealed
pressure tube at the given temperature for the given time, followed by flash chromatography on SiO2. Abbreviations: L = ligand, bipy = 2,2′-
b
c
d
bipyridine, nd = not determined. Isolated yield. Determined by chiral HPLC analysis. The yield of byproduct ethyl benzoate.
bis(oxazoline) ligands (BOX; L9 and L10) provided a significant
improvement in enatioselectivity (entries 12, 13, 15, and 16).
Among the tested PYOX and BOX ligands (L4−L10), L10
showed the best chiral induction ability (95% ee) in
comparison to any other tested ligand (entries 10−16).
Notably, evaluating phosphine-containing ligand L1 and other
oxazoline ligands (L2, L3, and L8) did not enable the
transformation to occur in the presence of Pd(OAc)2 (entries
7−9 and 14). Diminished enantioselectivities were observed
from the use of ligands (L5 and L8) that possess larger phenyl
substitutents at the 4- and 4′-positions of the oxazoline ring
(compared entries 11, 12, and 13; 14, 15, and 16). A catalyst
loading of 10 mol % was found to be effective to achieve higher
yield (compare entries 16 and 17). When the reaction
temperature was lowered to 50 °C, a satisfying yield (81%)
was obtained (compared entries 17 and 18). It is interesting
that utilizing 10 mol % of Pd(OAc)2 at 60 °C also provided a
13% yield of the byproduct ethyl benzoate (entry 17), which
most likely resulted from the direct esterification of phenyl-
boronic acids through the cleavage of carbonyl−imino σ bonds.
The optimal reaction conditions for the asymmetric arylation
of N-aryl-C-acylimine required 10 mol % of Pd(OAc)2, 10 mol
% of L10, and reaction temperature 50 °C. These catalytic
systems proved to be general for a variety of N-aryl
iminoacetates and arylboronic acids with excellent enantiose-
lectivity (up to 99% ee) (Table 2). We initiated a study where
we varied the N-aryl imino ester substrates. Aryl substitution on
the imine nitrogen (Ar1) shows no deleterious effects; both
para-electron-donating (4-MeO, 4-Me) and para-electron-
withdrawing (4-Cl, 4-Br, 4-NO2) groups all afforded the
corresponding α-amino esters (3a−f) in high yields (67−93%)
with over 95% ee (entries 1−6). In addition, an N-(m-
ethoxycarbonyl-substituted)aryl α-imino ester was also a
suitable substrate for this transformation (entry 7).
We next evaluated the electronic and steric effect of
substituents from arylboronic acids on the conversion and
enantioselectivity of the reaction. Electron-rich arylboronic
acids resulted in moderate to good yields (48−84%) with 84−
96% ee (entries 8−12), except for 4-hydroxyphenylboronic acid
(entry 13, 57% ee), and electron-deficient arylboronic acids
resulted in poor yields, but their enantioselectivities still
remained quite high (80−94%) (entries 14−17). The arylation
of α-imino ester with arylboronic acids bearing larger steric
bulkiness of ortho substituents or a naphthyl group also
proceeded successfully to give the corresponding α-amino
esters with high enantioselectivity (compare entries 10 and 11−
12; 1 and 19). Boronic acids with heteroaromatic rings such as
3-thienyl, 2-thienyl, and 3-furyl are also good substrates to give
the corresponding α-amino esters (3u−w) with 83−93% ee
(entries 21−23). Unfortunately, no reaction occurred for 2-
pyridylboronic acid,12 and α-imino ester 1a was completely
recovered (entry 20).
B
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a
Table 2. Pd(II)-Catalyzed Asymmetric Addition of Arylboronic Acids 2 to C-Acylimine 1
a
Reaction conditions: Pd(OAc)2 (0.01 mmol, 0.10 equiv) and L10 (0.01 mmol, 0.10 equiv) were combined, dissolved in CH3NO2 (3.0 mL), and
heated to 50 °C for 1 h. Then substrate 1 (0.1 mmol, 1.0 equiv) and 2 (0.1 mmol, 1.0 equiv) were added, and the reaction tube was sealed and
b
heated at 50 °C for 24 h unless otherwise noted. Abbreviations: L = ligand, nd = not determined. Yield refers to amount of isolated 3 after
c
d
purification by flash chromatography on SiO2. Determined by chiral HPLC analysis. The absolute configurations of 3a were determined by
comparing the optical rotation [α]D with known data. Assuming an analogous reaction mechanism, the configurations of other α-amino acid
e
f
g
h
derivatives are assigned as indicated in the table. Reaction time 15 h. 1.20 equiv of phenylboronic acid was used. Reaction time 36 h. Reaction
time 48 h.
C
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Scheme 2. Stereochemical Model
(IR) were recorded on a FT-IR spectrophotometer and are reported as
wavelength numbers (cm−1). Infrared spectra were recorded by
We determined the absolute stereochemistry of products 3a
via CAN deprotection of the PMP group and comparison with
the optical rotation and ee value of the respective known amino
ester (see the Experimental Section), and the absolute
configuration is in good agreement with the proposed
stereochemical model shown in Scheme 2. The imine nitrogen
coordinates with the palladium active species A which resulted
from palladium/L10 complexes and arylboronic acid 2a via
transmetalation.8,13 The aryl group preferred to add to the N-
arylimine carbon from the re face, avoiding the steric interaction
between the aryl section of the imino ester and aryl group on
Pd active species in a highly selective manner to produce (S)-
3a, which is similar to the arylation of N-sulfonylimines that
Nishimura, Zhou, and Lu previously reported.5j,8,14
1
preparing a KBr pellet containing the title compound. H and 13C
NMR spectra were recorded with tetramethylsilane (TMS) as internal
standard at ambient temperature unless otherwise indicated on a
standard spectrometer operating at 400 MHz for 1H and 100 MHz for
13C. Chemical shifts are reported in parts per million (ppm), and
coupling constants are reported as hertz (Hz). Splitting patterns are
designated as singlet (s), broad singlet (bs), doublet (d), and triplet
(t). Splitting patterns that could not be interpreted or easily visualized
are designated as multiplet (m). Melting points were determined on a
microscopic melting point apparatus and are uncorrected. Low-
resolution mass spectra were taken on a LC-MS instrument. High-
resolution mass spectra (HRMS) were recorded on a IF-TOF
spectrometer (Micromass). Enantiomeric excess values of all
compounds were obtained from chiral HPLC analyses, and the UV
detection was monitored at 254 nm. (S)-2-(4-phenyl-4,5-dihydroox-
azol-2-yl)pyridine17 (L5), (S)-2-(4-benzyl-4,5-dihydrooxazol-2-yl)-
pyridine17 (L6), (S)-2-(4-isopropyl-4,5-dihydrooxazol-2-yl)pyridine17
(L7), (S)-4-phenyl-2-((S)-4-phenyl-4,5-dihydrooxazol-2-yl)-4,5-dihy-
drooxazole18,19 (L8), (S,S)-4,4′-diisopropyl-4,5,4′,5′-tetrahydro[2.2]-
bioxazolyl18,19 (L10) and (R,R)-L1018,19 were prepared according to the
reported methods.
An illustration of the utility of this reaction is shown in the
concise asymmetric synthesis of 1-naphthyl-α-amino acid (3s-
2) and β-(1-naphthyl)-β-amino alcohol (3s-3) (Scheme 3).15
Scheme 3. Application of the Protocol in the Synthesis of
Enantiopure (1-Naphthyl)glycine and (1-Naphthyl)glycinol
a
General Procedures for the Synthesis of 3a−v. A mixture of
the substituted aniline (0.1 mmol, 12.3 mg), ethyl glyoxalate (1 equiv,
0.1 mmol, 10.2 mg), and anhydrous sodium sulfate (5 equiv, 0.5
mmol, 71 mg) in 2 mL of CH2Cl2 was stirred at room temperature for
0.5−3 h or refluxed in 2 mL of toluene at 110 °C for 1 h. Then the
corresponding mixture was cooled to room temperature and filtered,
and the filtrate was concentrated in vacuo without further purification
and used in the next step. Pd(OAc)2 (0.01 mmol, 0.1 equiv), (S,S)-
isopropyl bisoxazoline L10 (0.01 mmol, 0.1 equiv), and CH3NO2 (1.0
mL) were combined in a pressure tube equipped with a stir bar under
Ar, and the mixture was stirred at 45−50 °C for 1 h in order to make
the Pd(II) salt coordinate with the ligand completely. Then N-aryl α-
imino ester (0.1 mmol, 1.0 equiv) and arylboronic acid (0.1 mmol, 1.0
equiv) was added to the solution, and the tube was refreshed with Ar
for 5 min, sealed, and heated to 50 °C in an oil bath for the given time.
After the starting material has disappeared (monitored by TLC), the
reaction mixture was cooled to room temperature and then filtered,
the filtrate was concentrated in vacuo, and the corresponding crude
product was purified directly by silica gel column chromatography
(eluent consisting of hexane/EtOAc, from 20/1 to 15/1) to give the
pure product α-amino ester. The ee value of the product was
determined by chiral HPLC analysis and compared with the racemate.
(S)-Ethyl 2-(4-methoxyphenylamino)-2-phenylacetate (3a):3c
a
Legend: (a) CAN, CH3CN, room temperature, 12 h, 45% yield; (b)
HCl/H2O, reflux, 2.5 h, 96% yield; (c) NaBH4, CH3OH, room
temperature, 24 h, 83% yield.
The CAN deprotection reaction of 3s16 provided 1-naphthyl-α-
amino ester (3s-1) in 40% yield, and the following hydrolysis
and reduction of 3s-1 provided α-(1-naphthyl)-α-amino acid
(96% yield) and β-(1-naphthyl)-β-amino alcohol (83% yield),
respectively. This procedure was accomplished in just two steps
from readily available 3s and is several steps shorter than the
original route.15
In conclusion, we have developed a Pd(II)/chiral BOX
system -catalyzed asymmetric addition of arylboronic acids to
N-aryl-α-imino esters to yield the arylglycine derivatives with
high enantioselectivity. Removal of the PMP group can further
provide valuable chiral amino acids and chiral amino alcohols.
23.1 mg, 81% yield; [α]20 = +66.0° (c = 0.1, CHCl3); ee = 95%,
D
determined by HPLC analysis (Chiralcel AD-H, IPA 0.05 mL/min,
hexane 0.5 mL/min, λ 254 nm, t(minor) = 15.14 min, t(major) =
16.34 min); 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.5 Hz, 2 H),
7.36−7.30 (m, 3 H), 6.72 (d, J = 8.8 Hz, 2 H), 6.53 (d, J = 8.7 Hz, 2
H), 5.00 (s, 1 H), 4.67 (s, 1 H), 4.25−4.11 (m, 2 H), 3.70 (s, 3 H),
1.20 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm)
172.1, 152.5, 140.3, 137.9, 128.8, 128.2, 127.3, 114.8, 61.7, 61.6, 55.7,
14.1; MS (ESI) m/z 286.6 [M+], 324.6 [M + K+]; IR (KBr) 3399,
2927, 2854, 1734, 1513, 1457, 1370, 1305, 1239, 1178, 1029, 820, 732,
688, 523 cm−1.
EXPERIMENTAL SECTION
■
General Information. Unless otherwise noted, all other
commercially available reagents and solvents were used without
further purification. Purifications of reaction products were carried out
by flash chromatography using silica gel (40−63 mm). Infrared spectra
D
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(S)-Ethyl 2-(p-toluidino)-2-phenylacetate (3b):20 19.9 mg, 74%
(KBr) 3857, 3393, 2978, 2929, 1955, 1720, 1605, 1495, 1369, 1324,
1244, 1180, 1106, 1023, 867, 751, 696, 540 cm−1.
yield; [α]20 = +95.9° (c = 0.22, CHCl3); ee = 97%, determined by
D
(S)-Ethyl 2-(4-methoxyphenylamino)-2-p-tolylacetate (3h):3d
HPLC analysis (Chiralcel Lux 5u Cellulose-1, IPA 0.10 mL/min,
hexane 0.40 mL/min, λ 254 nm, t(minor) = 9.24 min, t(major) =
12.75 min); 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.4 Hz, 2 H),
7.37−7.28 (m, 3 H), 6.94 (d, J = 8.1 Hz, 2 H), 6.50 (d, J = 8.2 Hz, 2
H), 5.05 (s, 1 H), 4.83 (s, 1 H), 4.26−4.12 (m, 2 H), 2.21(s, 3 H),
1.22 (t, J = 8.0 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm)
172.0, 143.7, 137.9, 129.7, 128.8, 128.2, 127.3, 127.2, 113.6, 61.8, 61.1,
20.4, 14.1; MS (ESI) m/z 270.6 [M+], 292.5 [M + Na+], 308.6 [M +
K+]; IR (KBr) 3408, 2959, 2925, 2862, 1736, 1618, 1521, 1456, 1371,
1307, 1259, 1179, 1097, 1023, 807, 731, 698, 509 cm−1.
20.0 mg, 67% yield; [α]20 = +87.5° (c = 0.2, CHCl3); ee = 90%,
D
determined by HPLC analysis (Chiralcel AD-H, IPA 0.01 mL/min,
hexane 0.35 mL/min, λ 254 nm, t(minor) = 33.83 min, t(major) =
36.17 min); 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.8 Hz, 2 H),
7.16 (d, J = 7.8 Hz, 2 H), 6.73 (d, J = 8.7 Hz, 2 H), 6.55 (d, J = 8.7 Hz,
2 H), 4.98 (s, 1 H), 4.65 (s, 1 H), 4.25−4.11 (m, 2 H), 3.71 (s, 3 H),
2.34 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 172.2, 152.4, 140.4, 137.9, 134.9, 129.5, 127.1, 114.8, 114.7,
61.6, 61.4, 55.7, 21.2, 14.1; MS (ESI) m/z 300.6 [M+], 322.6 [M +
Na+]; IR (KBr) 3400, 2925, 2855, 1735, 1615, 1514, 1462, 1371, 1307,
1240, 1179, 1097, 1023, 807, 731, 698, 509 cm−1.
(S)-Ethyl 2-phenyl-2-(phenylamino)acetate (3c):21 17.1 mg. 67%
yield; [α]20 = +107.7° (c = 0.22, CHCl3); ee = 96%, determined by
D
(S)-Ethyl 2-(3-chlorophenyl)-2-(4-methoxyphenylamino)acetate
HPLC analysis (Chiralcel OD-H, IPA 0.01 mL/min, hexane 0.35 mL/
(3i):22 25.1 mg, 84% yield; [α]20 = +51.4° (c = 0.14, CHCl3); ee =
1
D
min, λ 254 nm, t(minor) = 18.42 min, t(major) = 16.03 min); H
96%, determined by HPLC analysis (Chiralcel AD-H, IPA 0.01 mL/
NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.7 Hz, 2 H), 7.37−7.26(m, 3
H), 7.11 (t, J = 7.7 Hz, 2 H), 6.73−6.70 (m, 1 H), 6.56 (d, J = 8.4 Hz,
2 H), 5.06 (d, J = 5.6 Hz, 1 H), 4.96 (s, 1H), 4.29−4.11 (m, 2 H), 1.23
(t, J = 12.0 Hz, 8.0 Hz, 3 H);13C NMR (100 MHz, CDCl3) δ (ppm)
171.9, 146.0, 137.8, 129.3, 128.8, 128.2, 127.2, 118.1, 113.4, 61.8, 60.8,
14.1; MS (ESI) m/z 256.5 [M+], 278.5 [M + Na+], 294.5 [M + K+];
IR (KBr) 3406, 3055, 3028, 2983, 2931, 1735, 1603, 1504, 1453, 1369,
1313, 1257, 1178, 1075, 1023, 872, 747, 695, 508 cm−1.
min, hexane 0.35 mL/min, λ 254 nm, t(minor) = 30.90 min, t(major)
1
= 34.88 min); H NMR (400 MHz, CDCl3) δ 7.35−7.19 (m, 3 H),
7.12 (d, J = 7.3 Hz, 1 H), 6.74 (d, J = 8.8 Hz, 2 H), 6.56 (d, J = 8.8 Hz,
2 H), 4.97 (s, 1 H), 4.65 (s, 1 H), 4.27−4.10 (m, 2 H), 3.71 (s, 3 H),
2.35 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 172.2, 152.5, 140.4, 138.5, 137.8, 129.0, 128.7, 127.8, 124.4,
114.9, 114.8, 61.8, 61.7, 55.7, 21.5, 14.1; MS (ESI) m/z 300.4 [M+],
322.4 [M + Na+], 338.3 [M + K+]; IR (KBr) 3400, 2956, 2924, 2855,
1735, 1608, 1514, 1461, 1374, 1301, 1241, 1189, 1160, 1030, 820, 739,
696, 515, 444 cm−1.
(S)-Ethyl 2-(4-chlorophenylamino)-2-phenylacetate (3d):20 27.0
mg, 93% yield; [α]20 = +97.5° (c = 0.2, CHCl3); ee = 97%,
D
determined by HPLC analysis (Chiralcel Lux 5u Cellulose-1, IPA 0.1
mL/min, hexane 0.4 mL/min, λ 254 nm, t(minor) = 9.94 min,
t(major) = 11.15 min); 1H NMR (400 MHz, CDCl3) δ 7.51−7.48 (m,
2 H), 7.37−7.30 (m, 3 H), 7.09−7.05 (m, 2 H), 6.51−6.47 (m, 2 H),
5.06−5.03 (m, 2 H), 4.29−4.11 (m, 2 H), 1.23 (t, J = 8.0, 4.0 Hz, 3H);
13C NMR (100 MHz, CDCl3) δ (ppm) 171.6, 144.5, 137.3, 129.0,
128.4, 127.2, 122.7, 114.5, 62.0, 60.8, 14.1; MS (ESI) m/z 290.5 [M+],
328.5 [M + K+]; IR (KBr) 3404, 2926, 2856, 1736, 1600, 1500, 1458,
1371, 1315, 1256, 1177, 1094, 1022, 816, 734, 698, 503 cm−1.
(S)-Ethyl 2-(4-bromophenylamino)-2-phenylacetate (3e):20 30.0
(S)-Ethyl 2-(4-methoxyphenyl)-2-(4-methoxyphenylamino)-
acetate (3j):3c 23.9 mg, 76% yield; [α]20 = +91.0° (c = 0.2,
D
CHCl3); ee = 93%, determined by HPLC analysis (Chiralcel AD-H,
IPA 0.20 mL/min, hexane 0.80 mL/min, λ 254 nm, t(minor) = 9.49
min, t(major) = 11.96 min); 1H NMR (400 MHz, CDCl3) δ 7.42 (d, J
= 8.3 Hz, 2 H), 7.26 (s, 1H), 6.89 (d, J = 8.3 Hz, 2 H), 6.73 (d, J = 8.6
Hz, 2 H), 6.55 (d, J = 8.6 Hz, 2 H), 4.97 (s, 1 H), 4.64 (s, 1 H), 4.23−
4.12 (m, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 2.06 (s, 1H), 1.22 (t, J =
7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 172.3, 159.5,
152.5, 140.4, 129.9, 128.4, 114.9, 114.8, 114.2, 61.6, 61.1, 55.7, 55.3,
14.1; MS (ESI) m/z 316.6 [M+], 338.6 [M + Na+]; IR (KBr) 3399,
2924, 2849, 1734, 1679, 1610, 1512, 1462, 1371, 1305, 1241, 1176,
1031, 823, 739, 527 cm−1.
mg, 90% yield; [α]20 = +79.5° (c = 0.22, CHCl3); ee = 98%,
D
determined by HPLC analysis (Chiralcel Lux 5u Cellulose-1, IPA 0.1
mL/min, hexane 0.4 mL/min, λ 254 nm, t(minor) = 10.22 min,
t(major) = 12.03 min); 1H NMR (400 MHz, CDCl3) δ 7.50−7.48 (m,
2 H), 7.39−7.30 (m, 3H), 7.22 − 7.18 (m, 2 H), 6.46−6.42 (m, 2 H),
5.07 (s, 1H), 5.03 (s, 1 H), 4.29−4.11 (m, 2 H), 1.22 (t, J = 8 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ (ppm) 171.5, 144.9, 137.2, 132.0,
128.9, 128.4, 127.2, 115.0, 109.8, 62.0, 60.7, 14.1; MS (ESI) m/z 334.5
[M+]; IR (KBr) 3400, 2926, 2855, 1735, 1652, 1595, 1457, 1369,
1309, 1240, 1021, 878, 772, 697, 502 cm−1.
(S)-Ethyl 2-(3-methoxyphenyl)-2-(4-methoxyphenylamino)-
acetate (3k):11b 22.1 mg, 70% yield; [α]20 = +61.0° (c = 0.2,
D
CHCl3); ee = 95%, determined by HPLC analysis (Chiralcel AD-H,
IPA 0.20 mL/min, hexane 0.80 mL/min, λ 254 nm, t(minor) = 6.69
min, t(major) = 7.67 min); 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J =
7.9 Hz, 1 H), 7.09−7.04 (m, 2 H), 6.84 (d, J = 8.1 Hz, 1 H), 6.72 (d, J
= 8.7 Hz, 2 H), 6.54 (d, J = 8.7 Hz, 2 H), 4.97 (s, 1H), 4.65 (s, 1 H),
4.25−4.09 (m, 2 H), 3.79 (s, 3 H), 3.71 (s, 3 H), 1.21 (t, J = 7.1 Hz, 3
H); 13C NMR (100 MHz, CDCl3) δ (ppm) 172.0, 160.0, 152.5, 140.3,
139.5, 129.8, 119.6, 114.9, 114.8, 113.7, 112.8, 61.7, 55.7, 55.3, 29.7,
14.1; MS (ESI) m/z 316.4 [M+], 338.4 [M + Na+]; IR (KBr) 3397,
2926, 2851, 2063, 1731, 1685, 1599, 1513, 1461, 1370, 1242, 1187,
1159, 1033, 822, 780, 739, 694, 522, 459 cm−1.
(S)-Ethyl 2-(4-nitrophenylamino)-2-phenylacetate (3f):20 27.0 mg,
90% yield; [α]20D = +244.5° (c = 0.22, CHCl3); ee = 99%, determined
by HPLC analysis (Chiralcel IC, IPA 10%, hexane 90%, 0.8 mL/min, λ
254 nm, t(minor) = 26.20 min, t(major) = 24.89 min); 1H NMR (400
MHz, CDCl3) δ 8.03−7.99 (m, 2 H), 7.47−7.44 (m, 2 H), 7.39−7.31
(m, 3 H), 6.52- 6.48 (m, 2 H), 5.87 (d, J = 5.3 Hz, 1 H), 5.12 (d, J =
5.7 Hz, 1 H), 4.31−4.11 (m, 2 H), 1.22 (t, J = 8.0 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 170.7, 150.9, 138.8, 136.1, 129.1, 128.8,
127.0, 126.2, 112.1, 62.5, 60.0, 14.0; MS (ESI) m/z 301.6 [M+], 339.5
[M + K+]; IR (KBr) 3779, 3403, 2923, 2854, 1734, 1668, 1601, 1513,
1460, 1373, 1309, 1240, 1179, 1028, 821, 754, 700, 503 cm−1.
(S)-Ethyl 3-(2-ethoxy-2-oxo-1-phenylethylamino)benzoate (3g).
colorless solid; mp 74−75 °C; 31.1 mg, 95% yield; [α]20D = +120.0° (c
= 0.22, CHCl3); ee = 94%, determined by HPLC analysis (Chiralcel
Lux 5u Cellulose-1, IPA 0.10 mL/min, hexane 0.40 mL/min, λ 254
(S)-Ethyl 2-(2-methoxyphenyl)-2-(4-methoxyphenylamino)-
acetate (3l):23 15.1 mg, 48% yield; [α]20 = +41.4° (c = 0.14,
D
CHCl3); ee = 84%, determined by HPLC analysis (Chiralcel AD-H,
IPA 0.01 mL/min, hexane 0.35 mL/min, λ 254 nm, t(minor) = 52.99
1
min, t(major) = 57.90 min); H NMR (400 MHz, CDCl3) δ 7.35−
7.33 (m, 1 H), 7.29−7.24 (m, 1 H), 6.93 (t, J = 7.6 Hz, 2 H), 6.74−
6.71 (m, 2 H), 6.63−6.59 (m, 2 H), 5.42 (s, 1 H), 4.59 (s, 1 H), 4.17−
4.11 (m, 2 H), 3.90 (s, 3 H), 3.71 (s, 3 H), 1.18 (t, J = 7.1 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ (ppm) 177.0, 157.2, 152.5, 140.8,
129.3, 128.1, 126.7, 121.0, 115.1, 114.8, 111.2, 61.3, 56.1, 55.7, 29.7,
14.1; MS (ESI) m/z 338.1 [M + Na+]; IR (KBr) 3388, 2924, 2852,
1734, 1672, 1599, 1512, 1462, 1371, 1242, 1188, 1026, 821, 747, 523
cm−1.
1
nm, t(minor) = 10.91 min, t(major) = 12.52 min); H NMR (400
MHz, CDCl3) δ 7.52−7.50 (m, 2 H), 7.39−7.29 (m, 5 H), 7.16 (t, J =
7.9 Hz, 1 H), 6.73−6.71 (m, 1 H), 5.17 (d, J = 6.1 Hz, 1 H), 5.12 (dd,
J = 19.3, 6.1 Hz, 1 H), 4.32 (q, J = 7.1 Hz, 2H), 4.25- 4.10 (m, 2 H),
1.36 (t, J = 8.0 Hz, 3 H), 1.22 (t, J = 8.0, 4.0 Hz, 3 H); 13C NMR (100
MHz, CDCl3) δ(ppm) 171. 6, 166.8, 146.0, 137.3, 131.4, 129.2, 128.9,
128.4, 127.2, 119.1, 117.6, 114.3, 61.9, 60.7, 29.7, 14.3, 14.0; HRMS
(EI) calcd for [M + Na]+ C19H21NO4 350.1363, found 350.1350; IR
(S)-Ethyl 2-(4-hydroxyphenyl)-2-((4-methoxyphenyl)amino)-
acetate (3m):11b 14.1 mg, 47% yield; [α]20 = +41.9° (c = 0.16,
D
CHCl3); ee = 57%, determined by HPLC analysis (Chiralcel AD-H,
IPA 0.20 mL/min, hexane 0.80 mL/min, λ 254 nm, t(minor) = 8.32
E
dx.doi.org/10.1021/jo301423e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
min, t(major) = 16.23 min); 1H NMR (400 MHz, CDCl3) δ 7.33 (d, J
= 8.4 Hz, 2 H), 6.75 (dd, J = 21.1, 8.7 Hz, 4 H), 6.54 (d, J = 8.8 Hz, 2
H), 4.93 (s, 1 H), 4.76 (d, J = 4.2 Hz, 0H), 4.63 (d, J = 4.0 Hz, 0.52 H)
+ 4.16 (ddt, J = 17.8, 14.2, 5.3 Hz, 0.4 H) = 1 H, 3.71 (s, 3 H), 1.20 (t,
J = 7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 172.4, 155.7, 152.5,
140.3, 129.8, 128.6, 115.7, 114.8, 114.9, 61.7, 61.2, 55.8, 14.1; MS
(ESI) m/z 302.1 [M+]; IR (KBr) 3652, 3396, 2952, 1730, 1610, 1559,
1513, 1459, 1380, 1240, 1169, 1026, 951, 819, 517 cm−1.
2855, 1735, 1599, 1504, 1474, 1371, 1318, 1260, 1178, 1138, 1110,
1020, 834, 734, 697, 495 cm−1.
(S)-Ethyl 2-(4-methoxyphenylamino)-2-(naphthalen-1-yl)acetate
(3s): yellow oil; 13.1 mg, 39% yield; [α]20D = +17.0° (c = 0.2, CHCl3);
ee = 93%, determined by HPLC analysis (Chiralcel Lux 5u Cellulose-
1, IPA 0.10 mL/min, hexane 0.40 mL/min, λ 254 nm, t(minor) =
1
14.46 min, t(major) = 17.55 min); H NMR (400 MHz, CDCl3) δ
8.32 (d, J = 8.4 Hz, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.83 (d, J = 8.2 Hz,
1 H), 7.64 (d, J = 7.2 Hz, 1 H), 7.61−7.51 (m, 2 H), 7.44 (t, J = 7.7
Hz, 1 H), 6.72 (d, J = 8.7 Hz, 2 H), 6.56 (d, J = 8.7 Hz, 2 H), 5.77 (s, 1
H), 4.72 (s, 1 H), 4.30−3.99 (m, 2 H), 3.70 (s, 3 H), 1.15 (t, J = 7.1
Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 172.4, 152.6, 140.5,
134.1, 133.7, 131.4, 129.0, 128.9, 126.5, 125.9, 125.5, 124.9, 123.5,
114.9, 114.6, 61.8, 58.4, 55.7, 14.0; HRMS (EI) calcd for [M + H]+
C21H21NO 336.1594, found 336.1597; IR (KBr) 2955, 2924, 2855,
1736, 1513, 1461, 1375, 1263, 1193, 1024, 740 cm−1.
(S)-Ethyl 2-(4-chlorophenyl)-2-(4-methoxyphenylamino)acetate
(3n):22 15.0 mg, 47% yield; [α]20 = +91.5° (c = 0.2, CHCl3); ee =
D
94%, determined by HPLC analysis (Chiralcel Lux 5u Cellulose-1, IPA
0.10 mL/min, hexane 0.40 mL/min, λ 254 nm, t(minor) = 12.34 min,
t(major) = 13.73 min); 1H NMR (400 MHz, CDCl3) δ 7.45 (d, J = 8.3
Hz, 2 H), 7.32 (d, J = 8.2 Hz, 2 H), 6.73 (d, J = 8.7 Hz, 2 H), 6.51 (d, J
= 8.7 Hz, 2 H), 4.98 (s, 1 H), 4.73 (s, 1 H), 4.25−4.12 (m, 2 H), 3.71
(s, 3 H),1.22 (m, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 171.5,
152.6, 139.9, 136.6, 134.0, 129.0, 128.6, 114.9, 114.8, 62.0, 61.1, 55.7,
14.1; MS (ESI) m/z 320.5 [M+], 342.5 [M + Na+]; IR (KBr) 3399,
2926, 2855, 1736, 1593, 1514, 1463, 1371, 1241, 1179, 1092, 1020,
820, 739, 508 cm−1.
(R)-Ethyl 2-(4-methoxyphenylamino)-2-(naphthalen-1-yl)acetate
(3s). (R,R)-L10 used as a chiral ligand; yellow oil; 13.1 mg, 39% yield;
[α]20 = −48.0° (c = 0.1, CHCl3); ee = 96%, determined by HPLC
D
analysis (Chiralcel Lux 5u Cellulose-1, IPA 0.10 mL/min, hexane 0.40
mL/min, λ 254 nm, t(major) = 15.24 min, t(minor) = 17.77 min).
We also increased the reaction scale to a gram scale in order to
further synthesize the corresponding free amino acid (3s-2) and amino
alcohol (3s-3). A mixture of 4-anisidine (5 mmol, 0.62 g), ethyl
glyoxalate (5 mmol, 0.51 g), and anhydrous sodium sulfate (25 mmol,
3.55 g) in 100 mL of CH2Cl2 was stirred at room temperature for 3 h.
Then the corresponding mixture was filtered, and the filtrate was
concentrated in vacuo without further purification and used in the next
step. Pd(OAc)2 (0.5 mmol, 0.1 equiv, 0.11 g), (S,S)-isopropyl
bisoxazoline L10 (0.5 mmol, 0.1 equiv, 0.11 g), and CH3NO2 (50
mL) were combined in a pressure tube equipped with a stir bar under
Ar, and the mixture was stirred at 50 °C for 2 h in order to make the
Pd(II) salt coordinate with the ligand completely. Then ethyl 2-((4-
methoxyphenyl)imino)acetate (5 mmol, 1.0 equiv, 1.04 g) and
naphthalen-1-ylboronic acid (5 mmol. 1.0 equiv, 0.86 g) were added
to the solution, and the tube was refreshed with Ar for 5 min and then
sealed and heated to 50 °C in an oil bath for 48 h. After the starting
material disappeared (monitored by TLC), the reaction mixture was
cooled to room temperature and then filtered, the filtrate was
concentrated in vacuo, and the corresponding crude product was
purified directly by silica gel column chromatography (eluent
consisting of hexane/EtOAc, from 20/1) to give 3s in 42% yield
with 95% ee.
(S)-Ethyl 2-(3-chlorophenyl)-2-(4-methoxyphenylamino)acetate
(3o): yellow oil; 12.1 mg, 38% yield; [α]20 = +29.0° (c = 0.2,
D
CHCl3); ee = 89%, determined by HPLC analysis (Chiralcel Lux 5u
Cellulose-1, IPA 0.10 mL/min, hexane 0.40 mL/min, λ 254 nm,
1
t(minor) = 13.16 min, t(major) = 15.32 min); H NMR (400 MHz,
CDCl3) δ 7.51 (s, 1 H), 7.39 (t, J = 3.6 Hz, 1 H), 7.33−7.21 (m, 2 H),
6.73 (d, J = 8.8 Hz, 2 H), 6.51 (d, J = 8.8 Hz, 2 H), 4.97 (s, 1 H), 4.73
(s, 1 H), 4.48−3.95 (m, 2 H), 3.71 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H);
13C NMR (100 MHz, CDCl3) δ (ppm) 171.4, 152.6, 140.12, 139.9,
134.7, 130.0, 128.4, 127.4, 125.4, 114.9, 114.8, 62.0, 61.3, 55.7, 14.0;
HRMS (EI) calcd for [M + Na]+ C17H18ClNO3 342.0867, found
342.0861; IR (KBr) 3395, 2924, 2854, 1737, 1671, 1593, 1514, 1463,
1373, 1240, 1183, 1094, 1025, 818, 751, 448 cm−1.
(S)-Ethyl 2-(4-fluorophenyl)-2-(4-methoxyphenylamino)acetate
(3p):22 17.9 mg, 59% yield; [α]20 = +57.5° (c = 0.2, CHCl3); ee =
D
94%, determined by HPLC analysis (Chiralcel Lux 5u Cellulose-1, IPA
0.10 mL/min, hexane 0.40 mL/min, λ 254 nm, t(minor) = 11.91 min,
t(major) = 13.05 min); 1H NMR (400 MHz, CDCl3) δ 7.50−7.47 (m,
2 H), 7.04 (t, J = 8.5 Hz, 2 H), 6.73 (d, J = 8.7 Hz, 2 H), 6.53 (d, J =
8.7 Hz, 2 H), 5.00 (s, 1 H), 4.72 (s, 1 H), 4.25−4.13 (m, 2 H), 3.71 (s,
3 H), 2.05 (s, 1H), 1.22 (t, J = 7.1 Hz, 3 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 171.8, 163.8, 161.4, 152.6, 140.0, 133.7, 133.7, 128.9,
128.8, 115.8, 115.6, 114.8, 114.7, 61.8, 61.0, 55.7, 14.0; MS (ESI) m/z
304.6 [M+], 326.6 [M + Na+]; IR (KBr) 3390, 2923, 2853, 1731, 1600,
1509, 1463, 1299, 1231, 1178, 1025, 816, 744, 514 cm−1.
(S)-Ethyl 2-(4-methoxyphenylamino)-2-(thiophen-3-yl)acetate
(3u): yellow oil; 18.0 mg, 62% yield; [α]20 = +23.5° (c = 0.2,
D
CHCl3); ee = 93%, determined by HPLC analysis (Chiralcel AD-H,
(S)-Ethyl 2-(4-methoxyphenylamino)-2-(4-(trifluoromethyl)-
phenyl)acetate (3q):3d 4.9 mg, 14% yield; [α]20 = +52.5° (c =
IPA 0.01 mL/min, hexane 0.35 mL/min, λ 254 nm, t(minor) = 46.28
D
1
0.04, CHCl3); ee = 80%, determined by HPLC analysis (Chiralcel Lux
min, t(major) = 53.32 min); H NMR (400 MHz, CDCl3) δ 7.34−
5u Cellulose-1, IPA 0.10 mL/min, hexane 0.40 mL/min, λ 254 nm,
7.30 (m, 2 H), 7.17 (d, J = 4.9 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 2 H), 6.59
(d, J = 8.8 Hz, 2 H), 5.13 (s, 1 H), 4.54 (s, 1 H), 4.32−4.10 (m, 2 H),
3.73 (s, 3 H), 1.25 (t, J = 7.2 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 171.8, 152.7, 140.4, 138.5, 126.5, 126.3, 122.8, 115.0, 114.9,
61.7, 58.1, 55.7, 14.1; HRMS (EI) calcd for [M + H]+ C15H17NO3S
292.1002, found 292.1004; IR (KBr) 3394, 2924, 2855, 1736, 1674,
1513, 1461, 1374, 1240, 1184, 1096, 1028, 878, 741 cm−1.
1
t(minor) = 12. 95 min, t(major) = 15.31 min); H NMR (400 MHz,
CDCl3) δ 7.62 (q, J = 8.4 Hz, 4 H), 6.72 (d, J = 8.5 Hz, 2 H), 6.72 (d,
J = 8.5 Hz, 2 H), 6.49 (d, J = 8.5 Hz, 2 H), 5.05 (s, 1 H), 4.80 (s, 1 H),
4.26−4.12 (m, 2 H), 3.70 (s, 3 H), 1.22 (t, J = 7.1 Hz, 3 H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 171.2, 152.7, 142.2, 139.7, 130.6, 130.2,
127.6, 125.8, 125.7,125.4, 122.7, 117.4, 114.9, 114.8, 62.1, 61.3, 55.7,
14.0; MS (ESI) m/z 353.0 [M+], 377.1 [M + Na+]; IR (KBr) 2924,
2854, 1738, 1673, 1617, 1514, 1461, 1374, 1325, 1241, 1168, 1128,
1067, 1021, 823, 742, 462 cm−1.
(S)-Ethyl 2-(4-methoxyphenylamino)-2-(thiophen-2-yl)acetate
(3v):24 9.9 mg, 34% yield; [α]20 = +16.4° (c = 0.14, CHCl3); ee =
D
83%, determined by HPLC analysis (Chiralcel AS-H,, IPA 5%, hexane
95%, 0.8 mL/min, λ 254 nm, t(minor) = 16.57 min, t(major) = 13.25
min); 1H NMR (400 MHz, CDCl3) δ 7.30−7.19 (m, 1 H), 7.13 (s, 1
H), 7.04−6.90 (m, 1 H), 6.76 (d, J = 8.7 Hz, 2 H), 6.63 (d, J = 8.5 Hz,
2 H), 5.26 (s, 1 H), 4.63 (s, 1 H), 4.35−4.08 (m, 2 H), 3.73 (s, 3 H),
1.27 (t, J = 6.6 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 171.1, 153.0,
141.6, 140.0, 127.0, 125.5, 125.4, 115.3, 114.9, 62.0, 58.0, 55.7, 14.1;
MS (ESI) m/z 314.3 [M + Na+], 330.4 [M + K+]; IR (KBr) 3383,
2925, 2855, 1738, 1671, 1513, 1462, 1373, 1240, 1183, 1023, 822, 741,
599, 541 cm−1.
(S)-Ethyl 2-([1,1′-biphenyl]-4-yl)-2-((4-methoxyphenyl)amino)-
acetate (3r): yellow oil; 30.0 mg, 83% yield; [α]20 = +63.0° (c =
D
0.2, CHCl3); ee = 95%, determined by HPLC analysis (Chiralcel Lux
5u Cellulose-1, IPA 0.10 mL/min, hexane 0.40 mL/min, λ 254 nm,
1
t(minor) = 16.30 min, t(major) = 17.19 min); H NMR (400 MHz,
CDCl3) δ 7.66−7.51 (m, 6 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.35 (t, J =
7.3 Hz, 1 H), 6.75 (d, J = 8.6 Hz, 2 H), 6.58 (d, J = 8.6 Hz, 2 H), 5.06
(s, 1 H), 4.73 (s, 1 H), 4.33−4.10 (m, 2 H), 3.72 (s, 3 H), 1.24 (t, J =
7.1 Hz, 3 H); 13C NMR (100 MHz, CDCl3) δ 172.0, 152.5, 141.1,
140.6, 140.3, 136.9, 128.8, 127.7, 127.5, 127.4, 127.1, 114.9, 114.8,
61.8, 61.5, 55.7, 14.1; HRMS (EI) calcd for [M + Na]+ C23H23NO3
384.1570, found 384.1574; 326.6 [M + Na]+; IR (KBr) 3380, 2925,
(S)-Ethyl 2-(furan-3-yl)-2-(4-methoxyphenylamino)acetate (3w):
yellow oil; 6.9 mg, 25% yield; [α]20D = +4.6° (c = 0.26, CHCl3); ee =
89%, determined by HPLC analysis (Chiralcel AD-H, IPA 0.05 mL/
F
dx.doi.org/10.1021/jo301423e | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
min, hexane 0.35 mL/min, λ 254 nm, t(minor) = 19.83 min, t(major)
= 22.82 min); 1H NMR (400 MHz, CDCl3) δ [7.47 (s, 0.3 H) + 6.47
(s, 0.3 H) + 6.35 (s, 1.4 H) + 7.39 (s, 1 H)] = 2 H, 6.76 (d, J = 8.3 Hz,
2 H), 6.63 (d, J = 8.3 Hz, 2 H), [5.13 (s, 0.7 H) + 4.98 (s, 0.3 H)] = 1
H, 4.53 (s, 1 H), 4.34−4.11 (m, 2 H), 3.73 (s, 3 H), 1.30−1.17 (m, 3
H); 13C NMR (100 MHz, CDCl3) δ 170.2, 153.0, 150.4, 143.4, 142.7,
140.5, 140.0, 115.4, 115.2, 114.9, 110.6, 109.4, 108.0, 62.0, 56.3, 55.7,
29.7, 14.1; HRMS (EI) calcd for [M + Na]+ C15H17NO4 298.1050,
found 298.1055; IR (KBr) 3379, 2924, 2854, 1739, 1672, 1513, 1462,
1373, 1240, 1183, 1023, 822, 741, 599, 541 cm−1.
EtOH)); 1H NMR (400 MHz, CDCl3) δ 7.83−7.55 (m, 5 H), 4.95 (s,
1 H), 4.62−4.42 (m, 2 H), 2.37 (s, 2 H), 1.56 (t, J = 7.1 Hz, 3 H); MS
(ESI) m/z 180.4 [M+], 202.4 [M + Na+], 218.5 [M + K+].
ASSOCIATED CONTENT
* Supporting Information
■
S
Tables and figures giving details of the experimental conditions,
1H and 13C NMR spectra for all isolated compounds, and
HPLC traces for determinations of the enantiomeric excess.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(S)-Ethyl 2-amino-2-(naphthalen-1-yl)acetate (3s-1).25 A CH3CN
(5.0 mL) solution of (S)-ethyl 2-(4-methoxyphenylamino)-2-(naph-
thalen-1-yl)acetate (3s; 67.0 mg, 0.2 mmol) was cooled to 0 °C, an
aqueous solution of ammonium cerium nitrate (CAN, 484 mg, 0.88
mmol, 3.0 mL of H2O) was added directly, and the corresponding
mixture was stirred at ambient temperature for 12 h, and then its pH
was adjusted to 1 using aqueous HCl solution (2 N). After the
aqueous phase was washed with EtOAc (3 × 8 mL) and brought to
basic by the addition of saturated NaHCO3, the resulting suspension
was extracted with CH2Cl2 (3 × 12 mL) and dried over anhydrous
Na2SO4, and then the crude product was purified directly by silica gel
AUTHOR INFORMATION
Corresponding Author
*E-mail: zengwei@scut.edu.cn.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
column chromatography to afford 21 mg (45% yield) of 3s-1: [α]20
=
■
D
+29.6° (c = 0.24, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J =
8.4 Hz, 1 H), 7.88 (d, J = 7.8 Hz, 1 H), 7.82 (dd, J = 6.3, 3.0 Hz, 1 H),
7.61−7.41 (m, 4 H), 5.32 (s, 1 H), 4.34−4.05 (m, 2 H), 2.00 (s, 2 H),
1.16 (t, J = 7.1 Hz, 3 H); MS (ESI) m/z 231.0 [M+], 253.0 [M + Na+];
IR (KBr) 3862, 3748, 3679, 3615, 3053, 2924, 2855, 1735, 1672, 1512,
1460, 1371, 1301, 1211, 1163, 1104, 1025, 954, 784, 729, 520, 470
cm−1.
We thank the Program for New Century Excellent Talents in
University by Ministry of Education (No. NCET-10-0371), the
NSFC (No. 21072063), RFDP (No. 20100172120020), and
Guangdong Natural Science Foundation (No.
10351064101000000) for financial support.
REFERENCES
■
(S)-2-Amino-2-(naphthalen-1-yl)acetic acid hydrochloride (3s-
2).26 (S)-Ethyl 2-amino-2-(naphthalen-1-yl)acetate (3s-1; 22.9 mg,
0.10 mmol) was refluxed in hydrochloric acid (1.5 mL, 4.0 M) for 2.5
h. Then the mixture was washed with diethyl ether and concentrated
under vacuum to yield 22.8 mg (96% yield) of 3s-2 as a colorless solid:
[α]20D = +85.0° (c = 0.24, MeOH); 1H NMR (400 MHz, D2O) δ 8.01
(d, J = 8.4 Hz, 1 H), 7.92 (dd, J = 12.4, 8.4 Hz, 2 H), 7.60−7.44 (m,
4H), 5.88 (s, 1 H); MS (ESI) m/z 224.7 [M − HCl + Na+]; IR (KBr)
3462, 2922, 2852, 1636, 1411, 1266, 1211, 743, 531, 460 cm−1.
(S)-2-Amino-2-(naphthalen-1-yl)ethanol (3s-3).27 A MeOH (6
mL) solution of (S)-ethyl 2-amino-2-(naphthalen-1-yl)acetate (3s-1;
62 mg, 0.27 mmol) was cooled to 0 °C, and then NaBH4 (55 mg, 1.62
mmol) was added in one portion. The resulting solution was stirred
under ambient temperature for 24 h. After the reaction was complete
(monitored by TLC), the organic solvents were evaporated under
vacuum. Water (5 mL) was added, and after phase separation the
corresponding aqueous phase was extracted with EtOAc (3 × 3 mL).
The combined organic extracts were washed with brine, dried
(Na2SO4), and then concentrated under high vacuum. The crude
product was purified directly by silica gel column chromatography to
give 42.0 mg (83% yield) of 3s-3: [α]20D = +17.1° (c = 0.14, CHCl3);
1H NMR (400 MHz, CDCl3) δ 8.11 (d, J = 8.2 Hz, 1 H), 7.88 (d, J =
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7.56−7.46 (m, 3 H), 4.93 (s, 1 H), 3.95 (s, 1 H), 3.77−3.59 (m, 1 H),
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(S)-Ethyl 2-amino-2-phenylacetate (3a-1).25 The absolute config-
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D
D
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The Journal of Organic Chemistry
Article
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D
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H
dx.doi.org/10.1021/jo301423e | J. Org. Chem. XXXX, XXX, XXX−XXX